Miniaturized QC testing of PET tracers

Overview

QC Testing

After synthesis and purification, PET tracers are formulated in saline, sometimes with an additive such as ethanol or ascorbic acid to mitigate the effects of radiolysis. Before the PET tracer can be administered to a patient, the final batch must be subjected to several quality control (QC) tests to ensure that it is safe for injection.

Required tests depend on the particular tracer, the method of synthesis, and the regulations of the country in which the tracer is produced, but essentially consist of the following:

Most tests are required before release of the tracer, but there are exceptions. For example, if the filter integrity test passes, the tracer can be released without completion of the sterility test (the test takes much longer to complete than the lifetime of the tracer).

Problems with current QC strategies and methodologies:

Expensive equipment (various expensive instruments are needed)

Bulky equipment (QC testing requires a small room or dedicated area of the lab)

Requires skilled pesonnel (operator must be train in use of all instruments, calibration, documentation etc.)

Solutions

Currently there are a couple of groups developing automated systems that include all needed equipment and perform most required tests in an automated fashion (QC1, ABT Molecular Technologies, Inc., and Trace-Ability). These systems also aliquot the original sample to the various subsystems that perform different tests.

In addition to automation, we are interested in miniaturized technologies which have additional potential advantages:

One of the most expensive pieces of equipment is the radio-HPLC. We are initially focused on finding a miniaturized replacement for tests involving this instrument. Another technique with good separating power is capillary electrophoresis (CE) (Wikipedia article) . CE has the advantage that it can be implemented in compact microfluidic chips and requires a relatively small power supply and detection system. We explored the feasibility of separating PET tracers from impurities using this approach to assess radiochemical and chemical purity.

Using a conventional CE system with UV detection, we have demonstrated the ability to perform chemical identity and purity analysis of the PET tracers [F-18]FLT and [F-18]FAC . Using micellar electrokinetic chromatography (MEKC) by adding SDS to a neutral phosphate buffer, the separation of all compounds in the samples were achieved with baseline resolutions within < 4.5 min and 3 min for FLT and FAC samples, respectively. In comparison to the HPLC with UV detection (the gold standard for chemical analysis of many PET tracers), we have demonstrated improvements in analysis times and comparable limits of detection. In addition, we showed that CE can be used to identify and quantify K222 (a toxic and commonly used phase transfer catalyst) in less than 2 min. These results demonstrate adequate performance for chemical identity and purity analysis using CE.

Current Status and Future Directions

We are currently translating these preliminary findings into a microfluidic platform with integrated UV detection cell to reduce the system size, improve the injection performance, and improve the limit of detection. We are also investigating: